1. Field of the Invention
The present invention relates to a method for enhancing gut absorption in a mammal suffering from a pathological condition which is characterized by decreased absorptive property of the gut. The invention further relates to a method for hastening the weaning of a mammal.
2. Description of the Background Art
A. Pathological Conditions
Many pathological conditions lead to decreased absorptive properties of the gut. These pathological conditions are known collectively as malabsorption syndrome. Table 1 summarizes the various disorders which can lead to malabsorption syndrome.
TABLE 1 ______________________________________ Disorders Which Cause Malabsorption Syndrome ______________________________________ I. Inadequate absorptive surface A. Intestinal resection or bypass 1. Mesenteric vascular disease with massive intestinal resection 2. Regional enteritis with multiple bowel resections 3. Jejunoileal bypass B. Gastroileostomy (inadvertent) II. Lymphatic obstruction A. Intestinal lymphangiectasia B. Whipple's disease C. Lymphoma III. Cardiovascular disorders A. Constrictive pericarditis B. Congestive heart failure C. Mesenteric vascular insufficiency D. Vasculitis IV. Primary mucosal absorptive defects A. Inflammatory or infiltrative disorders 1. Regional enteritis 2. Amyloidosis 3. Scleroderma 4. Lymphoma 5. Radiation enteritis 6. Eosinophilic enteritis 7. Tropical sprue 8. Infectious enteritis (e.g., salmonellosis) 9. Collagenous sprue 10. Nonspecific ulcerative jejunitis 11. Mastocytosis 12. Dermatologic disorders (e.g., dermatitis herpetiformis) B. Biochemical or genetic abnormalities 1. Nontropical sprue (gluten-induced enteropathy); celiac sprue 2. Disaccharide deficiency 3. Hypogammaglobulinemia 4. Abetalipoproteinemia 5. Hartnup disease 6. Cystinuria 7. Monosaccharide malabsorption V. Endocrine and metabolic disorders A. Diabetes mellitus B. Hypoparathyroidism C. Adrenal insufficiency D. Hyperthyroidism E. Ulcerogenic tumor of the pancreas (Zollinger- Ellison syndrome, gastrinoma) F. Carcinoid syndrome ______________________________________
One most severe condition is short gut syndrome (SGS). SGS is a result of therapeutic surgical excision of a majority of the small intestine. SGS has been recognized as a pathological state for the past twenty years and is estimated to currently affect 17,000 people nationally.
A variety of acute pathological conditions may result in SGS. These include meconium ileus, volvulus, gastroschisis, necrotizing enterocolitis and Hirschprung's disease. If less than 75 cm of small bowel remains, significant malabsorption may occur (Schwartz M. Z., et al. Ped. Clin. North Amer. 32: 1265-1279 (1985)).
The above table provides a portion of the many pathological conditions which can cause malabsorption syndrome for a more detailed review see Greenberg, N. J. et al. Harrison p. 1260. Gillin (Gillin J. S. et al. Ann. Int. Med. 102: 619 (1985)) has observed that AIDS can be a causal agent of malabsorption syndrome. This generally is known as AIDs mediated diarrhea and sometimes can be associated with an infectious agent.
Patients with malabsorption syndrome have a difficult time meeting daily nutritional requirements. In patients with malabsorption syndrome there generally exists both catabolic and serious nutritional consequences. As a result, most patients with malabsorption syndrome require total parenteral nutrition (TPN).
At present, the nutritional requirements of patients who are unable to feed themselves adequately are met through the administration of enteral or parenteral diets. Enteral diets are usually administered using small-bore tubing which is placed through the nose into the gastric, or duodenal regions, or through surgical implantation as in, for example, gastrostomy, or jejunostomy. Those enteral formulas which are presently available can be divided into four basic categories: elemental, polymeric, modular, and altered amino acids. These formulae contain glutamine (GLN). The levels of nutrients present in the enteral diets, however, are generally based upon the dietary requirements of a normal individual and not that of a patient suffering from a catabolic disease.
Elemental formulas require minimal digestive action and are composed primarily of small peptides and/or amino acids, glucose oligosaccharides, and vegetable oil or medium-chain triglycerides.
In polymeric formulas, complex nutrients such as, for example, soy protein, lactalbumin, or casein are utilized as a source of protein; maltodextrins or corn syrup solids as a source of carbohydrate; and vegetable oils or milk fat as a source of fat.
Modular diets can be produced by combining protein, carbohydrate, or fat with a monomeric or polymeric formula to meet special nutritional requirements.
Formulas which are composed of altered amino acid compositions are used primarily for patients with genetic errors of nitrogen metabolism or acquired disorders of nitrogen accumulation, the object often being to limit the intake by the patient of certain amino acids which may be detrimental.
Parenteral diets are usually administered intravenously (i.v.). These i.v. fluids are sterile solutions composed of simple chemicals such as, for example, sugars, amino acids, and electrolytes, which can be easily assimilated.
The term "total parenteral nutrition" (TPN) is used to describe formulas for use in patients who derive their entire dietary requirements i.v. Total parenteral nutrition formulas, unlike enteral formulas, do not normally contain GLN. The absence of GLN from parenteral formulas is due, in part, to concern with respect to its instability at room temperature, and the resulting generation of ammonia and pyroglutamic acid. There has also been concern about the generation of glutamic acid from GLN because of the potential toxicity of glutamic acid as a neurotransmitter.
There is one major drawback with placing patients with malabsorption syndrome on TPN. TPN results in villus atrophy, a phenomenon which is generally reversible when oral feedings are resumed. Since most malabsorption syndrome patients are not placed back on oral feeding, TPN will generally accelerate villus atrophy and hence decrease the absorptive property of the gut in these patents.
Malabsorption syndrome often affects children and requires surgery. Following surgery, such children often spend months in the hospital because of instability of fluid and electrolyte status and the need for central intravenous nutrition. Rickets may also be observed in some children. Although central hyperalimentation may be managed at home, such care is associated with significant stress on the family unit. In addition, complications of this therapy including catheter-related infection and thrombosis are not uncommon. Management of these children is based upon the provision of adequate nutrition to achieve somatic growth and hopefully, growth of the absorptive surface of the intestinal remnant so that oral alimentation may be accomplished.
B. Growth Hormone and Gut Development
There is mounting evidence that growth hormone (GH) appears to be necessary for the growth and differentiation of transplanted rat intestine in early neonatal life. (Cooke P. S., et al., Biol. Neonate 49: 211-218 (1986)). Lehy et al. (Lehy T. et al., Gastroenterology 90: 646-653 (1986)) recently reported that subcutaneous GH-releasing hormone increased DNA synthesis and mitotic activity in fundal and duodenal rat mucosa. Whether this is a direct effect of GH-releasing hormone upon intestinal mucosa or mediated indirectly through stimulation of GH secretion or another factor is not evident.
Additional studies have indicated the ability of GH to stimulate intestine growth and increase absorptive properties. Collie et al. demonstrated that GH pellets implanted in salmon for two weeks resulted in a 30% increase in intestinal dry weight (Collie N. L., et al., Gen. Comp. Endocrinol. 59: 399-409 (1985)). In addition, Mainoya has shown that ovine GH stimulates absorption of water and sodium in proximal rat jejunum and distal ileum (Mainoya J. R., Comp. Biochem. Physiol. 71(a): 477-479 (1982); Spencer E. M., et al. Endocrinology 108: 1064-1070 (1981); Bruns M. E., et al. Endocrinology 113: 1387-1392 (1983); Aloia J. F., et al., Bone 6: 73-77 (1985)).
The potential benefits of growth hormone therapy upon intestinal growth, and mineral and water homeostasis in infants and small children with malabsorption syndrome who are dependent on intravenous hyperalimentation has not yet been investigated. Since no toxicity has been observed in GH therapy in dosages of 0.75 U/kg/wk in the treatment of girls with gonadyl dysgenesis (Rosenfeld R. G., et al., J. Pediatr. 109:936-43 (1986)), GH appears to be a potential agent for the treatment of children with malabsorption syndrome. Specifically, if a significant therapeutic effect of GH, were observed in children with malabsorption syndrome considerable morbidity and the cost associated with prolonged hospitalization, intravenous hyperalimentation and family stress might by lessened by the addition of this agent to current therapy.
The present invention is the first to combine the use of GLN for increasing gut absorptive properties (for example see U.S. Pat. No. 4,857,555) with the suspected therapeutic benefits of GH for stimulating intestinal growth and increasing the absorptive properties of the gut. The present invention discloses the unexpected results that GLN and GH act synergistically, and when administered to a patient with malabsorption syndrome, can ultimately lead to removal of the patients from intravenous feeding onto an oral diet .